The mechanisms underlying the effects of alcohol abuse and smoking on the development of pancreatitis are poorly understood. Recent epidemiologic studies demonstrate that smoking accelerates the development of pancreatitis in alcoholic patients and may have an additive or multiplicative effect when combined with alcohol abuse to cause pancreatitis. We have recently demonstrated that alcohol metabolism causes an oxidative stress in the endoplasmic reticulum (ER) of the exocrine pancreatic acinar cell and that the acinar cell adapts to this stress through a system of adaptive responses in the ER called the Unfolded Protein Response (UPR). Specific genetic alteration to block an alcohol metabolism-dependent upregulation of spliced X-box binding protein 1 (XBP1-S), a key UPR regulator, induced dysregulation of the adaptive UPR, ER dysfunction and acinar cell pathology. These results suggest a central role of ER stress and the UPR induced by alcohol metabolism in the mechanism of pancreatitis due to alcohol abuse. Based on preliminary studies using smoking compounds we hypothesize that smoking compounds augment the development of alcoholic pancreatitis by accelerating redox disorders in the Endoplasmic Reticulum (ER) of the acinar cell and preventing key responses of the Unfolded Protein Response (UPR) from adapting the cell to the combination of both environmental stressors. To address this hypothesis, we propose both in vitro and in vivo models of alcohol abuse and smoking with measurements of ER stress, UPR and pathologic responses. Importantly, we plan to also use state-of-the-art approaches in chemistry and mass spectroscopy to assess alterations in key oxido-reductases that are essential for post- translational modifications of proteins in the lumen of the ER caused by alcohol abuse and smoking. Our approach is designed to reveal the consequences of alcohol and smoking compound metabolism in the ER of the acinar cell including both adaptive mechanisms and failure of the adaptive responses leading to pathologic consequences. The results will provide novel understanding on the early cellular events involved in diseases resulting from alcohol and smoking addiction and as such will provide opportunities for designing clinical interventions. Furthermore, our results should have broad ranging impacts on a variety of disorders related to abuse of these substances.